Short syntheses of polyhydroxylated α-alkylated amino acids

Full text of DOI:10.1021/jo980205e

4524
J . Org. Chem. 1998, 63, 4524-4528
Sh or t Syn th eses of P olyh yd r oxyla ted
r-Alk yla ted Am in o Acid s†
Roland Grandel, Uli Kazmaier,* and Frank Rominger
Organisch-Chemisches Institut der Universita¨t,
Im Neuenheimer Feld 270,
D-69120 Heidelberg, Federal Republic of Germany
Received February 4, 1998
In tr od u ction
Polyhydroxylated amino acids are an important class
of natural products (Figure 1). Polyoxamic acid is part
of many polyoxines, which are potent antifungal agents.1
Polyhydroxylated amino acids are also substructures of
the sphingofungines, another family of antifungal com-
pounds.2 Among them, R-alkylated amino acids are
important as well. Myriocin,3 for example, shows very
high immunosuppressive activity. In addition, polyhy-
droxylated amino acids are valuable tools in the design
of polyhydroxylated piperidine alkaloids.2b,4
F igu r e 1. Naturally occurring polyhydroxylated amino acids.
For some time, our group has been interested in
reactions of metal-chelated enolates of N-protected amino
acid esters.5 Depending on the metal salt used, these
chelated enolates show higher stability than the corre-
sponding lithium enolates. In addition, because of the
fixed enolate geometry, their reactions are more selective
than those of the lithium enolates. Besides chelate
enolate Claisen rearrangements, aldol reactions give
especially good results.6 A very high simple diastereo-
selectivity of >95% is obtained in the reactions of
N-sulfonylated amino acid esters in the presence of 2.5
equiv of SnCl2, with both aliphatic as well as aromatic
aldehydes.7 This protocol can be applied to various types
of amino acids, and the selectivities observed are nearly
independent of the sulfonyl protecting group used. In
cases where the tosyl group is difficult to remove, the
F igu r e 2. Chiral aldehydes used in asymmetric aldol reac-
tions.
easier to cleave 2-(trimethylsilyl)ethanesulfonyl (SES)
protecting group, developed by Weinreb et al.,8 can be
used.7
Resu lts a n d Discu ssion
Herein, we present the results of an asymmetric
version of this reaction.9 In addition to auxiliary con-
trolled reactions, especially the use of chiral aldehydes
is suitable for this purpose.10 In aldol reactions of chiral
R-alkoxy or R-siloxy aldehydes (Figure 2), an induction
on the newly formed chiral center in general is observed,
and this chirality transfer should be used in the synthesis
of optically active polyhydroxylated amino acids.
Deprotonation of N-protected alanine esters (5 and 6)
with LDA at -78 °C and subsequent addition of metal
salts presumably results in the formation of a chelated
enolate (Scheme 1), which can be trapped with a chiral
aldehyde (1-4).
† Dedicated to Prof. R. W. Hoffmann on the occasion of his 65th
birthday.
(1) (a) Isono, K.; Suzuki, S. Heterocycles 1979, 13, 333. (b) Isono,
K.; Asahi, K.; Suzuki, S. J . Am. Chem. Soc. 1969, 91, 7490. (c) Mori,
M.; Kakiki, K.; Misato, T. Agric. Biol. Chem. 1974, 38, 699. (d) Becker,
J . M.; Covert, N. L.; Shenbagamurthi, P. S.; Steinfeld, A.; Naider, F.
Antimicrob. Agents Chemother. 1983, 23, 926.
Depending on the metal salt used, two aldol products,
out of the four possible stereoisomers, were formed
preferentially (Table 1). The best results by far were
obtained with >2 equiv of tin chloride (Table 1, entries
3, 4, 6, and 7). In comparison to reactions with less than
2 equiv of metal salt (Table 1, entries 2 and 5), the
selectivity in the aldol addition is dramatically increased.
This is, in general, true for the simple diastereoselectivity
(relation a /b) and the induced diastereoselectivity (ds)
of the aldol products a and b as well. This is in good
agreement with observations made earlier.7 In compari-
son, other metal salts such as zinc chloride react less
selectively, and the four stereoisomers were formed in
comparable amounts. Therefore, the zinc enolates were
used to obtain a mixture of all possible isomers for
analytical purposes.11 The simple diastereoselectivities
observed were nearly independent of the aldehyde em-
ployed in the aldol reaction, and the highly oxygenated
(2) (a) VanMiddlesworth, F.; Giacobbe, R. A.; Lopez, M.; Garrity,
G.; Bland, J . A.; Bartizal, K.; Fromtling, R. A.; Polishook, J .; Zweerink,
M.; Edison, A. M.; Rozdilsky, W.; Wilson, K. E.; Monaghan, R. L. J .
Antibiot. 1992, 45, 861. (b) VanMiddlesworth, F.; Dufresne, C.; Wincott,
F. E.; Mosley, R. T.; Wilson, K. E. Tetrahedron Lett. 1992, 33, 297.
(3) (a) Bagli, J . F.; Kluepfel, D. J . Org. Chem. 1973, 38, 1253. (b)
Fijita, T.; Inoue, K.; Yamamoto, S.; Ikumoto, T.; Sasaki, S.; Toyoma,
R.; Chiba, K.; Hoshino, J .; Okumoto, T. J . Antibiot. 1994, 47, 208.
(4) Park, K. H.; Yoon, Y. J .; Lee, S. G. J . Chem. Soc., Perkin Trans.
1 1994, 2621.
(5) Kazmaier, U. Liebigs Ann./Recl. 1997, 285.
(6) (a) Kazmaier, U.; Grandel, R. Synlett 1995, 945. (b) Grandel,
R.; Kazmaier, U.; Nuber, B. Liebigs Ann./ Recl. 1996, 1143.
(7) Grandel, R.; Kazmaier, U. Eur. J . Org. Chem. 1998, 409.
(8) Weinreb, S. M.; Demko, D. M.; Lessen, T. A. Tetrahedron Lett.
1986, 27, 2099.
(9) Grandel, R.; Kazmaier, U. Tetrahedron Lett. 1997, 38, 8009.
(10) (a) Heathcock, C. H. In Modern Synthetic Methods 1992;
Scheffold, R., Ed.; VHCA/VCH: Basel, Weinheim, 1992; p 3. (b) Braun,
M. In Houben-Weyl: Methods of Organic Synthesis-Stereoselective
Synthesis; Helmchen, G., Hoffmann, R. W., Mulzer, J ., Schaumann,
E., Eds.; Thieme: Stuttgart, 1996, 1603, 1713 and references therein.
(11) The product mixtures were analyzed by HPLC and NMR.
S0022-3263(98)00205-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/11/1998

Notes
J . Org. Chem., Vol. 63, No. 13, 1998 4525
Ta ble 1. Ald ol Rea ction s of Meta l En ola tes of Ts-a la n in e Ester s 5 a n d 6 w ith th e Ald eh yd es 1-4
entry
aldehyde
ester
MXn (equiv)
product
a :ba
a (% ds)
b (% ds)
yield (%)
1
2
3
4
5
6
7
1
1
1
2
3
3
4
5
5
5
6
5
5
6
ZnCl2 (2.5)
SnCl2 (1.2)
SnCl2 (2.5)
SnCl2 (2.5)
SnCl2 (1.2)
SnCl2 (2.5)
SnCl2 (2.5)
7
7
7
8
9
55:45
59:41
81:19
89:11
67:33
78:22
80:20
58
66
95
>99
76
15
90
74
88
85
82
>99
>99
>99
9
10
95
94
90
87
a
Based on HPLC of the crude reaction mixture.
Sch em e 1
Sch em e 2
Sch em e 3
aldehydes 3 and 4 in particular showed excellent induced
selectivities.
Therefore, and with respect to the good yields obtained,
this procedure allows a straightforward and highly
stereoselective synthesis of R-alkylated polyhydroxylated
amino acids.12 These amino acids can also be used for
the construction of cyclic oxygenated amino acids such
as prolines or pipecolinic acid, interesting classes of
potential glycosidase inhibitors.9 This was one reason
we decided to convert the aldol product 10 into the
corresponding pipecolinic acid derivative. The other
reason was the necessity to confirm the configuration of
our products and to determine the selectivities observed.
For this purpose, the pipecolinic acid derivatives are
especially suitable. Due to the chair conformation, it
should be relatively easy to reliably determine the
orientation of the substituents by NMR.
Starting from the crude aldol product 9, diastereomeri-
cally pure 9a could be obtained by a single crystallization
step. The pure minor diastereomer 9b could be obtained
from the mother liquid by flash chromatography. After
cleavage of the benzyl ether, the alcohol 11a obtained
was first converted into the corresponding mesylate.2b
Unfortunately, this derivative was not a suitable precur-
sor for the required cyclization. Therefore, the alcohols
11a and 11b were subjected directly to the Mitsunobu
reaction,13 which gave the tosylated14 pipecolinic acid
derivatives 12a and 12b, respectively, in good to excellent
yields (Scheme 2).15
These cyclic derivatives could also be used to determine
the configuration of the two new stereogenic centers
formed in the aldol reaction. Scheme 3 shows the
coupling constants (in Hz) and the NOEs observed.
The configuration of the â-hydroxy group was con-
firmed from the coupling constant of the hydrogen at C3
to the adjacent proton at C4. Because of the ketal moiety,
this proton has to be oriented in an axial position.
Coupling constants of 2.3 and 2.6 Hz, respectively, are
typical for protons in an axial/equatorial orientation.
Therefore, the hydroxy groups in 12a and 12b as well
are oriented in an axial position. This clearly indicates
that the induced diastereoselectivity in the aldol reaction
was excellent and that both diastereomers obtained have
different configurations at the R-position (C2) (simple
diastereomers). This was also confirmed by NOE experi-
ments.
(12) In contrast, reaction of glycin enolates gave a 1:1 diastereomeric
mixture at the R center, probably because of epimerization under the
reaction conditions used.
(13) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Henry, J . R.; Marcin,
L. R.; McIntosh, M. C.; Scola, P. M.; Harris, G. D.; Weinreb, S. M.
Tetrahedron Lett. 1989, 30, 5709. (c) Simon, C. J . Heterocycl. Chem.
1997, 34, 349.
(14) Reductive cleavage of the tosyl group: Xu, Y.-M.; Zhou, W.-S.
J . Chem. Soc., Perkin Trans. 1 1997, 741.
(15) Recent syntheses of comparable piperidine derivatves: (a)
Altenbach, H.-J .; Wischnat, R. Tetrahedron Lett. 1995, 36, 4983. (b)
Xu, Y.-M.; Zhou, W.-S. Tetrahedron Lett. 1996, 37, 1461.

4526 J . Org. Chem., Vol. 63, No. 13, 1998
Notes
Ta ble 3. Selected 1H NMR a n d 13C NMR Sign a ls (p p m )
of Ald ol P r od u cts 7-10
7
8
9
10
a
b
a
b
a
b
a
b
CH3
OH
NH
1.21
3.46
6.09
1.40
2.57
6.15
1.34
3.27
6.02
1.49
2.67
5.91
1.32
3.65
6.07
1.43
3.62
5.92
1.29
3.53
6.15
1.48
2.63
5.87
CH3
R-C
â-C
γ-C
20.45 18.11 20.48 18.99 19.53 17.40 19.56 17.01
64.82 64.62 64.63 63.60 65.57 65.44 64.91 64.27
79.18 77.71 79.82 78.64 79.98 79.00 77.44 75.16
76.35 76.41 70.90 69.40 77.15 77.09 75.47 172.21
C)O 171.49 172.17 172.52 172.69 170.64 171.40 171.97 172.21
Con clu sion
In summary, we have shown that aldol reactions of
tosylated amino acid ester enolates with chiral aldehydes
give rise to polyhydroxylated amino acid esters in a
straightforward and highly stereoselective fashion.
R-Alkylated pipecolinic acid esters can be obtained via
cyclization under Mitsunobu conditions. In these deriva-
tives, strong interactions between the tosyl protecting
group and substituents at the R-position are observed.
The question if these sterical interactions can be used
as stereocontrolling elements is currently under inves-
tigation.
F igu r e 3. Crystal structure of pipecolic acid derivative 12a .
Ta ble 2. Bon d An gles of Nitr ogen a n d Its Neigh bor In g
Atom s in P ip ecolic Acid Der iva tive 12a
bond angle (deg)
C6-N-C2
S-N-C2
S-N-C6
118.9(0.1)
121.1(0.1)
113.5(0.1)
Exp er im en ta l Section
Irradiation into the R-methyl group of 12a gave two
NOEs, one to the vicinal equatorial â-H (C3) and the
second to an aromatic proton in the ortho position of the
tosyl group. In the same experiment, 12b showed three
NOEs. Interactions are observed to the axially oriented
protons at C4 and C6 and to the â hydrogen as well. This
can be explained by an axial orientation of the methyl
group in 12b, while in 12a the methyl group is orientated
in the equatorial position.
Gen er a l P r oced u r e. General procedures and methods for
characterization have been described previously.18 1H and 13C
NMR spectra were recorded in CDCl3 (if not noted otherwise)
on a Bruker AC-200 or AC-300 spectrometer, respectively.
Diastereomeric ratios were determined by analytical HPLC
using a Knauer Eurosphere column (250 × 4 mm, Si80, 5 µm,
flow; 2 mL/min) or a Daicel Chiralcel OD-H column. Optical
rotations were measured using a Perkin-Elmer 241 polarimeter.
The aldehydes used in the aldol reactions were prepared
according to the literature.
The configuration of this pipecolinic acid derivative
(12a ) could also be confirmed by X-ray structure analysis
(Figure 3).16 The pseudo planar environment of the
nitrogen atom (Table 2) leads to a torsion angle between
the sulfonyl group and the methyl substituent at C2 of
45°. The expectable interactions between these two
groups results in a bond angle at nitrogen of ap-
proximately 121°. Similar interactions obviously also
occur in solution, as indicated by a strong NOE between
the R-methyl substituent and the aromatic protons of the
tosyl group.
X-r a y Cr ysta l a n d In ten sity Da ta . A colorless crystal of
size 0.5 × 0.46 × 0.35 mm of compound 12a was mounted and
aligned on a Siemens CCD diffractometer. Crystal data: ortho-
rhombic; a ) 11.1402(2) Å, b ) 11.4909(2) Å, c ) 18.0835(4) Å;
space group P212121, V ) 2314.9(1) Å3, Z ) 4. Intensity data in
the 2θ range 4.20-51.02° were collected using the ω scan with
Mo KR radiation (λ ) 0.710 73 Å). A total of 3882 reflections
were collected, of which 3704 have shown I > 2σ(I).
All crystallographic calculations were carried out with the aid
of the Siemens SHELXTL program package. The positional and
anisotropic thermal parameters were refined for all non-
hydrogen atoms. The hydrogens were refined isotropically. For
the observed data final R ) 2.47%, Rw(F 2) ) 6.0%, goodness of
fit ) 1.05.
These results allow the determination of the 2,3-anti-
3,4-anti configuration for the major aldol product 9a and
the 2,3-syn-3,4-anti configuration for the minor diaste-
reomer 9b. The 2,3-anti-3,4-anti diastereomer as the
major aldol product is in accordance with the Felkin-
Anh model.17 The configuration of the other aldol
products was confirmed by comparison of the correspond-
ing NMR spectra. Comparable shifts for the signals of
the protons and the substituents at the R- and â-positions
were observed in the 1H NMR spectra (Table 3). The
same trends were also observed in the 13C NMR spectra.
(()-ter t-Bu tyl 2-[(4-tolu en esu lfon yl)a m in o]p r op a n oa te
(5). A solution of (()-tert-butyl 2-[(4-benzyloxycarbonyl)amino-
]propanoate19 (5 g, 18 mmol) in THF was hydrogenated in the
presence of 70 mg of 10% Pd/C for 24 h. The mixture was
filtered, and NEt3 was added, followed by 4-toluenesulfonyl
chloride at 0 °C. After 5 h, the mixture was washed with 1 N
HCl and saturated NaHCO3 solution. The combined organic
extracts were dried over Na2SO4, and the solvent was evapo-
rated. Flash chromatography (hexanes/ethyl acetate 8:2, 7:3)
yielded 4.4 g (81%) of a colorless solid, which was crystallized
1
from dichloromethane/hexanes: mp 88-89 °C; H NMR δ 1.27
(s, 9H), 1.34 (d, J ) 7.1 Hz, 3H), 2.39 (s, 3H), 3.84 (dq, J ) 8.6,
7.2 Hz, 1H), 5.22 (d, J ) 8.6 Hz, 1H), 7.27 (d, J ) 8.5 Hz, 2H),
7.72 (d, J ) 8.3 Hz, 2H); 13C NMR δ 20.07, 21.43, 27.65, 51.97,
82.34, 127.27, 129.62, 137.00, 143.48, 171.30. Anal. Calcd for
(16) The authors have deposited X-ray structure data at the
Cambridge Cystallographic Data Centre. These data can be obtained,
on request, from the Director, Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(17) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199. (b) Anh, N. T.; Eisenstein, O. Nouv. J . Chim 1977, 1, 61. (c) Anh,
N. T. Top. Curr. Chem. 1980, 88, 145.
C
14H21NO4S (299.39): C, 56.16; H, 7.07; N, 4.68. Found: C,
56.24; H, 7.06; N, 4.61.
(19) Mori, M.; Chiba, K.; Okita, M.; Kayo, I.; Ban, Y. Tetrahedron
1985, 41, 375.
(18) Kazmaier, U. J . Org. Chem. 1994, 59, 6667.

Notes
Gen er a l P r oced u r e for Ald ol Rea ction s. In a typical
J . Org. Chem., Vol. 63, No. 13, 1998 4527
oa te (9). According to the general procedure, the aldol reaction
of N-(4-toluenesulfonyl)alanine tert-butyl ester (5) (240 mg, 0.80
mmol) with aldehyde 322 (240 mg, 0.96 mmol) afforded 292 mg
(66%) of 9a and 82 mg (19%) of 9b after flash chromatography
(hexanes/ethyl acetate (1) 9:1, (2) 8:2, (3) 7:3).
experiment, a solution of 1 mmol of LDA in 2 mL of anhydrous
THF was added at -78 °C under argon to a solution of 0.4 mmol
of N-tosylated amino acid ester and 190 mg (1 mmol) of SnCl2
in 2 mL of THF. In general, a clear orange solution was formed.
After 10 min, a solution of 0.48 mmol of the aldehyde in 1 mL of
THF was added. After 30 min at -78 °C, the reaction was
quenched by adding phosphate buffer pH 7. The mixture was
diluted with diethyl ether and was allowed to warm to rt. After
filtration of the mixture through a pad of Celite, the aqueous
phase was extracted twice with diethyl ether. The combined
organic extracts were washed with brine and dried over Na2-
SO4, and the solvent was evaporated. The crude aldol product
was purified by flash chromatography.
ter t-Bu tyl 4-(Ben zyloxy)-3-h yd r oxy-2-m eth yl-2-[(4-tolu -
en esu lfon yl)a m in o]p en ta n oa te (7). According to the general
procedure, the aldol reaction of N-(4-toluenesulfonyl)alanine tert-
butyl ester (5) (268 mg, 0.80 mmol) with aldehyde 120 (158 mg,
0.96 mmol) yielded after flash chromatography (hexanes/ethyl
acetate 8:2) a mixture of the two major diastereomers (7a and
7b) (328 mg, 88%), which could be separated by flash chroma-
tography (hexanes/ethyl acetate, 85:15).
9a : crystallization from dichloromethane/hexanes; mp 115-
117 °C; [R] -32.7 (c ) 0.2, CHCl3); 1H NMR δ 1.32, 1.36, 1.38
(3s, 9H), 1.43 (s, 9H), 2.41 (s, 3H), 3.65 (d, J ) 10.2 Hz, 1H),
3.66 (dd, J ) 10.1, 6.0 Hz, 1H), 3.75 (dd, J ) 10.1, 3.5 Hz, 1H),
3.85 (dd, J ) 10.2, 9.1 Hz, 1H), 3.97 (dd, J ) 9.1, 7.7 Hz, 1H),
4.20 (ddd, J ) 7.7, 6.0, 3.6 Hz, 1H), 4.62 (s, 2H), 6.07 (s, 1H),
7.27 (d, J ) 7.1 Hz, 2H), 7.31-7.36 (m, 5H), 7.76 (d, J ) 8.3 Hz,
2H); 13C NMR δ 19.53, 21.49, 26.81, 26.91, 27.79, 65.57, 71.03,
73.59, 77.05, 77.10, 79.98, 83.26, 109.78, 126.78, 127.66, 127.81,
128.39, 129.60, 137.83, 139.73, 143.36, 170.64; HRMS (FAB)
calcd for C28H40NO8S [M+ + H] 550.2475, found 550.2493. Anal.
Calcd for C28H39NO8S (549.68): C, 61.18; H, 7.15; N, 2.55.
Found: C, 60.90; H, 7.02; N, 2.44.
9b: colorless oil; [R] -11.6 (c ) 0.2, CHCl3); 1H NMR δ 1.34,
1.38 (2s, 6H), 1.41 (s, 9H), 1.42 (s, 3H), 2.38 (s, 3H), 3.53 (dd, J
) 9.3, 6.6 Hz, 1H), 3.62-3.68 (m, 2H), 3.71 (dd, J ) 9.4, 4.4 Hz,
1H), 3.95 (dd, J ) 8.1, 7.7 Hz, 1H), 4.11 (ddd, J ) 7.4, 6.6, 4.4
Hz, 1H), 4.55 (d, J ) 12.1 Hz, 1H), 4.61 (d, J ) 12.1 Hz, 1H),
5.92 (s, 1H), 7.22-7.34 (m, 7H), 7.76 (d, J ) 8.3 Hz, 2H); 13C
NMR δ 17.40, 21.44, 26.70, 27.78, 65.44, 70.38, 73.82, 77.09,
78.59, 79.00, 82.75, 109.91, 127.18, 127.97, 128.08, 128.57,
129.35, 136.94, 140.01, 142.93, 171.40; HRMS (FAB) calcd for
C28H39NO8SNa [M+ + Na] 572.2294, found 572.2320.
Ben zyl 4,5-(sop r op ylid en ed ioxy)-3-h yd r oxy-2-m eth yl-2-
[(4-tolu en esu lfon yl)a m in o]p en ta n oa te (10). According to
the general procedure, the aldol reaction of N-(4-toluenesulfo-
nyl)alanine benzyl ester (6) (134 mg, 0.40 mmol) with aldehyde
423 (104 mg, 0.80 mmol) provided 135 mg (73%) of 10a and 27
mg (14%) of 10b after flash chromatography (hexanes/ethyl
acetate (1) 8:2, (2) 7:3).
10a : crystallization from dichloromethane/hexanes; mp 90-
91 °C; [R] -67.7 (c ) 0.5, CHCl3); 1H NMR δ 1.28, 1.29, 1.33 (3s,
9H), 2.40 (s, 3H), 3.53 (d, J ) 11.7 Hz, 1H), 3.79 (dd, J ) 11.7,
8.7 Hz, 1H), 4.00 (dd, J ) 8.5, 5.2 Hz, 1H), 4.17 (dd, J ) 8.5, 6.5
Hz, 1H), 4.24 (ddd, J ) 8.6, 6.5, 5.1 Hz, 1H), 4.97 (d, J ) 12.3
Hz, 1H), 5.2 (d, J ) 12.3 Hz, 1H), 6.15 (s, 1H), 7.24-7.34 (m,
7H), 7.73 (d, J ) 8.3 Hz, 2H); 13C NMR δ 19.56, 21.53, 24.87,
26.24, 64.91, 67.78, 68.13, 75.47, 77.44, 109.73, 126.79, 127.96,
128.60, 128.69, 129.74, 134.66, 139.33, 143.61, 171.97. Anal.
Calcd for C23H29NO7S (463.55): C, 59.60; H, 6.31; N, 3.02.
Found: C, 59.55; H, 6.29; N, 2.96.
10b: crystallization from dichloromethane/hexanes; mp 115-
116 °C; [R] -16.4 (c ) 0.2, CHCl3); 1H NMR δ 1.27, 1.36, 1.48
(3s, 9H), 2.38 (s, 3H), 2.63 (d, J ) 4.9 Hz, 1H), 3.81 (dd, J ) 5.1,
4.4 Hz, 1H), 3.91-4.35 (m, 3H), 5.00 (d, J ) 12.3 Hz, 1H), 5.08
(d, J ) 12.3 Hz, 1H), 5.87 (s, 1H), 7.22 (d, J ) 8.4 Hz, 2H), 7.24-
7.35 (m, 5H), 7.71 (d, J ) 8.3 Hz, 2H); 13C NMR δ 17.01, 21.53,
25.34, 26.36, 64.27, 66.19, 67.80, 75.16, 76.29, 108.19, 127.21,
128.05, 128.45, 128.58, 129.52, 135.01, 139.01, 143.40, 172.21.
Anal. Calcd for C23H29NO7S (463.55): C, 59.60; H, 6.31; N, 3.02.
Found: C, 59.71; H, 6.39; N, 2.97.
(2R,3S,4S,5S)-ter t-Bu tyl 4,5-(sop r op ylid en d ioxy)-3,6-d i-
h yd r oxy-2-m et h yl-2-[(4-t olu en esu lfon yl)a m in o]h exa n o-
a te (11a ). A solution of 9a (1.00 g, 1.82 mmol) in methanol was
hydrogenated in the presence of 50 mg of 10% Pd/C. After being
stirred for 24 h, the mixture was filtered and the solvent was
evaporated, giving rise to a colorless solid (784 mg, 94%), which
was crystallized from dichloromethane/hexanes: mp 171-172
°C; [R] -36.4 (c ) 0.6, CHCl3); 1H NMR δ 1.30 (s, 3H), 1.33,
1.36 (2s, 6H), 1.42 (s, 9H), 2.39 (s, 3H), 2.68 (mc, 1H), 3.79 (dd,
J ) 11.8, 4.8 Hz, 1H), 3.84 (J ) 11.8, 5.2 Hz, 1H), 3.90-4.00
(m, 3H), 4.05 (mc, 1H), 6.08 (s, 1H), 7.28 (d, J ) 8.2 Hz, 2H),
7.75 (d, J ) 8.3 Hz, 2H); 13C NMR δ 19.80, 21.53, 26.76, 26.90,
27.79, 63.12, 65.39, 76.49, 78.06, 81.35, 83.61, 109.34, 126.70,
129.72, 139.45, 143.59, 170.50. Anal. Calcd for C21H33NO8S
(459.56): C, 54.88; H, 7.24; N, 3.05. Found: C, 54.88; H, 7.27;
N, 2.87.
7a : colorless solid, which was crystallized from dichlo-
romethane/hexanes; mp 83-84 °C; [R] +51.1 (c ) 0.4, CHCl3);
1H NMR δ 1.21 (s, 3H), 1.23 (s, 9H), 1.34 (d, J ) 5.4 Hz, 3H),
2.42 (s, 3H), 3.46 (d, J ) 12.4 Hz, 1H), 3.64-3.80 (m, 2H), 4.41
(d, J ) 11.2 Hz, 1H), 4.49 (d, J ) 11.2 Hz, 1H), 6.09 (s, 1H),
7.27-7.36 (m, 7H), 7.76 (d, J ) 8.3 Hz, 2H); 13C NMR δ 17.22,
20.45, 21.50, 27.59, 64.82, 71.57, 76.35, 79.18, 82.95, 126.73,
127.77, 128.23, 128.93, 129.67, 137.91, 139.95, 143.31, 171.49;
HRMS (FAB) calcd for C24H33NO6SNa [M+ + Na] 486.1926,
found 486.1900. Anal. Calcd for C24H33NO6S (463.59): C, 62.17;
H, 7.18; N, 3.02. Found: C, 62.38; H, 7.12; N, 2.90.
1
7b: colorless oil; [R] +24.1 (c ) 1.0, CHCl3); H NMR δ 1.28
(d, J ) 5.8 Hz, 3H), 1.40 (s, 3H), 1.41 (s, 9H), 2.37 (s, 3H), 2.57
(bs, 1H), 3.60-3.70 (m, 2H), 4.43 (d, J ) 11.2 Hz, 1H), 4.55 (d,
J ) 11.2 Hz, 1H), 6.15 (s, 1H), 7.22 (d, J ) 8.3 Hz, 2H), 7.24-
7.37 (m, 5H), 7.71 (d, J ) 8.3 Hz, 2H); 13C NMR δ 16.07, 18.11,
21.45, 27.79, 64.62, 70.78, 76.41, 77.71, 83.04, 127.03, 127.88,
128.00, 128.50, 129.37, 137.57, 140.04, 142.93, 172.17; HRMS
(FAB) calcd for C24H34NO6S [M+ + H] 464.2106, found 464.2137.
Ben zyl 4-O-[(ter t-Bu tyld im eth ylsilyl)oxy]-3-h yd r oxy-2-
m eth yl-2-[(4-tolu en esu lfon yl)a m in o]p en ta n oa te (8). Ac-
cording to the general procedure, the aldol reaction of N-(4-
toluenesulfonyl)alanine benzyl ester (6) (134 mg, 0.40 mmol)
with aldehyde 221 (106 mg, 0.48 mmol) yielded 8 (167 mg, 85%).
The diastereomers were separated by flash chromatography
(hexanes/ethyl acetate 85:15).
8a : colorless oil; [R] +69.6 (c ) 1.9, CHCl3); 1H NMR δ 0.12,
014 (2s, 6H), 0.89 (s, 9H), 1.31 (d, J ) 6.1 Hz, 3H), 1.34 (s, 3H),
2.41 (s, 3H), 3.27 (d, J ) 11.6 Hz, 1H), 3.71 (dd, J ) 11.6, 8.0
Hz, 1H), 3.98 (dq, J ) 8.0, 6.1 Hz, 1H), 5.07 (d, J ) 12.3 Hz,
1H), 5.17 (d, J ) 12.3 Hz, 1H), 6.02 (s, 1H), 7.20-7.38 (m, 7H),
7.77 (d, J ) 8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ -4.44,
-3.77, 18.11, 20.48, 21.50, 21.62, 26.11, 64.63, 67.76, 70.90,
79.82, 126.91, 127.97, 128.49, 128.60, 129.62, 135.07, 139.73,
143.37, 172.52; HRMS (FAB) calcd for C26H40NO6SSi [M+ + H]
522.2346, found 522.2301.
8b: colorless oil; [R] +14.5 (c ) 0.8, CHCl3); 1H NMR δ 0.03,
0.05 (2s, 6H), 0.86 (s, 9H), 1.17 (d, J ) 6.3 Hz, 3H), 1.49 (s, 3H),
2.40 (s, 3H), 2.67 (d, J ) 3.9 Hz, 1H), 3.66 (dd, J ) 4.3, 3.9 Hz,
1H), 3.92 (dq, J ) 6.3, 4.3 Hz, 1H), 5.03 (d, J ) 12.4 Hz, 1H),
5.13 (d, J ) 12.4 Hz, 1H), 5.91 (s, 1H), 7.22 (d, J ) 8.0 Hz, 2H),
7.25-7.39 (m, 5H), 7.72 (d, J ) 8.3 Hz, 2H); 13C NMR δ -4.76,
-4.40, 17.84, 17.98, 18.99, 21.50, 25.80, 63.60, 67.61, 69.40,
78.64, 127.22, 128.04, 128.53, 129.40, 129.68, 135.32, 139.56,
143.05, 172.69; HRMS (FAB) calcd for C26H40NO6SSi [M+ + H]
522.2346, found 522.2324.
ter t-Bu tyl 6-O-(Ben zyloxy)-4,5-(isop r op ylid en ed ioxy)-3-
h yd r oxy-2-m e t h yl-2-[(4-t olu e n e su lfon yl)a m in o]h e xa n -
(20) Ito, Y.; Kobayashi, T.; Kawabata, M.; Takase, M.; Terashima,
S. Tetrahedron 1989, 45, 5767.
(21) Li, W.; Ewing, W. R.; Harris, B. D.; J oullie, M. M. J . Am. Chem.
Soc. 1990, 112, 7659.
(22) Mukaiyama, T.; Suzuki, K.; Yamada, T.; Tabusa, F. Tetrahedron
1990, 46, 265.
(23) Mulzer, J . In Organic Synthesis Highlights; Mulzer, J ., Alten-
bach, H.-J ., Braun, M., Krohn, K., Reissig, H.-U., Eds.; VCH: Wein-
heim, 1991; p 243.

4528 J . Org. Chem., Vol. 63, No. 13, 1998
Notes
(2S,3S,4S,5S)-ter t-Bu tyl 4,5-(Isop r op ylid en d ioxy)-3,6-d i-
h yd r oxy-2-m et h yl-2-[(4-t olu en esu lfon yl)a m in o]h exa n o-
a te (11b). According to the synthesis of 11a , 317 mg (0.58
mmol) of 9b was hydrogenated to yield 260 mg (98%) of a
colorless oil: [R] -13.3 (c ) 0.3, CHCl3); 1H NMR δ 1.23 (s, 3H),
1.37, 1.40 (2s, 6H), 1.43 (s, 9H), 1.50-1.80 (m, 2H), 2.39 (s, 3H),
3.70 (d, J ) 8.5 Hz, 1H), 3.77 (d, J ) 4.4 Hz, 2H), 3.88 (dd, J )
8.5, 7.7 Hz, 1H), 4.07 (td, J ) 7.7, 4.4 Hz, 1H), 5.94 (s, 1H), 7.26
(d, J ) 8.2 Hz, 2H), 7.76 (d, J ) 8.3 Hz, 2H); 13C NMR δ 17.46,
21.49, 26.74, 26.85, 27.76, 62.80, 65.13, 77.00, 78.67, 80.51, 83.44,
109.74, 127.42, 129.48, 139.68, 143.22, 171.73; HRMS (FAB)
calcd for C21H34NO8S [M+ + H] 460.2005, found 460.2038.
(2R,3S,4R,5S)-2-(ter t-Bu tyloxyca r bon yl)-4,5-(isop r op yli-
d en d ioxy)-3-h yd r oxy-2-m eth yl-1-(4-tolu en esu lfon yl)p ip e-
r id in e (12a ). To a solution of 11a (167 mg, 0.36 mmol) in 15
mL of THF was added PPh3 (143 mg, 0.55 mmol) at rt before
DEAD (80 µL, 0.51 mmol) was added dropwise as slowly as
possible. After complete addition, the mixture was stirred for
30 min and the solvent was evaporated. The residue obtained
was stirred with hexanes/ethyl acetate 9:1 and filtered. After
flash chromatography (hexanes/ethyl acetate 8:2, 7:3), 146 mg
(92%) of a colorless solid was obtained. Crystallization from
dichloromethane/hexanes afforded colorless rhombes: mp 126-
128 °C; [R] +42.6 (c ) 1.8, CHCl3); 1H NMR δ 1.41, 1.45 (2s,
6H), 1.46 (s, 9H), 1.61 (s, 3H), 2.40 (mc, 1H), 2.39 (s, 3H), 3.29
(dd, J ) 11.8, 11.0 Hz, 1H), 3.36 (dd, J ) 9.6, 2.6 Hz, 1H), 3.90
(ddd, J ) 11.0, 9.6, 4.8 Hz, 1H), 4.39 (d, J ) 2.6 Hz, 1H), 4.49
(dd, J ) 12.1, 4.8 Hz, 1H), 7.25 (d, J ) 8.0 Hz, 2H), 7.72 (d, J )
8.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 21.45, 22.10, 26.52,
26.72, 27.74, 49.14, 69.16, 69.34, 71.92, 79.39, 83.19, 110.98,
126.81, 129.44, 139.89, 143.14, 170.72; HRMS (FAB) calcd for
C
21H32NO7S [M+ + H] 442.1900, found 442.1890. Anal. Calcd
for C21H31NO7S (441.54): C, 57.13; H, 7.08; N, 3.17. Found: C,
57.18; H, 7.04; N, 3.10.
(2S,3S,4R,5S)-2-(ter t-Bu tyloxyca r bon yl)-4,5-(isop r op yli-
d en d ioxy)-3-h yd r oxy-2-m eth yl-1-(4-tolu en esu lfon yl)p ip e-
r id in e (12b). According to the synthesis of 12a , 260 mg (0.56
mmol) of 11b was reacted with PPh3 (224 mg, 0.86 mmol) and
DEAD (124 µL, 0.79 mmol). After flash chromatography (hex-
anes/ethyl acetate 8:2, 7:3), a colorless oil (186 mg, 75%) was
1
obtained: [R] +32.1 (c ) 1.0, CHCl3); H NMR δ 1.39, 1.42 (2s,
6H), 1.52 (s, 9H), 1.70 (s, 3H), 2.41 (s, 3H), 3.12 (dd, J ) 11.3,
11.0 Hz, 1H), 3.32 (d, J ) 2.1 Hz, 1H), 3.51 (dd, J ) 10.8, 4.6
Hz, 1H), 3.64 (dd, J ) 9.3, 2.3 Hz, 1H), 3.96 (ddd, J ) 11.3, 9.3,
4.6 Hz, 1H), 4.06 (dd, J ) 2.3, 2.0 Hz, 1H), 7.28 (d, J ) 8.0 Hz,
2H), 7.92 (d, J ) 8.3 Hz, 2H); 13C NMR δ 20.15, 21.30, 26.30,
26.58, 27.56, 46.64, 67.40, 68.75, 72.02, 78.05, 83.29, 111.49,
128.16, 129.25, 135.98, 143.69, 169.67; HRMS (FAB) calcd for
C21H31NO7SNa [M+ + Na] 464.1719, found 464.1718.
Ack n ow led gm en t. We thank Prof. Dr. G. Helmchen
for his generous support of this work. Financial support
by the Deutsche Forschungsgemeinschaft and the Fonds
der Chemischen Industrie is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Crystallographic
data for 12a (6 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O980205E